tbuckley/cabot-search huggingface dataset:
Current Knowledge About the Impact of Maternal and Infant Nutrition on the Development of the Microbiota–Gut–Brain Axis
Authors: Tomás Cerdó, Ana Nieto-Ruíz, José Antonio García-Santos, Anna Rodríguez-Pöhnlein, María García-Ricobaraza, Antonio Suárez, Mercedes G. Bermúdez, Cristina Campoy
Journal: Annual Review of Nutrition (2023)

The prenatal and early postnatal periods are stages during which dynamic changes and the development of the brain and gut microbiota occur, and nutrition is one of the most important modifiable factors that influences this process. Given the bidirectional cross talk between the gut microbiota and the brain through the microbiota–gut–brain axis (MGBA), there is growing interest in evaluating the potential effects of nutritional interventions administered during these critical developmental windows on gut microbiota composition and function and their association with neurodevelopmental outcomes. We review recent preclinical and clinical evidence from animal studies and infant/child populations. Although further research is needed, growing evidence suggests that different functional nutrients affect the establishment and development of the microbiota–gut–brain axis and could have preventive and therapeutic use in the treatment of neuropsychiatric disorders. Therefore, more in-depth knowledge regarding the effect of nutrition on the MGBA during critical developmental windows may enable the prevention of later neurocognitive and behavioral disorders and allow the establishment of individualized nutrition-based programs that can be used from the prenatal to the early and middle stages of life.
Genetic Architecture of Flowering Time Differs Between Populations With Contrasting Demographic and Selective Histories
Authors: Célia Neto, Angela Hancock
Journal: Molecular Biology and Evolution (2023)

Understanding the evolutionary factors that impact the genetic architecture of traits is a central goal of evolutionary genetics. Here, we investigate how quantitative trait variation accumulated over time in populations that colonized a novel environment. We compare the genetic architecture of flowering time in Arabidopsis populations from the drought-prone Cape Verde Islands and their closest outgroup population from North Africa. We find that trait polygenicity is severely reduced in the island populations compared to the continental North African population. Further, trait architectures and reconstructed allelic histories best fit a model of strong directional selection in the islands in accord with a Fisher-Orr adaptive walk. Consistent with this, we find that large-effect variants that disrupt major flowering time genes (FRI and FLC) arose first, followed by smaller effect variants, including ATX2 L125F, which is associated with a 4-day reduction in flowering time. The most recently arising flowering time-associated loci are not known to be directly involved in flowering time, consistent with an omnigenic signature developing as the population approaches its trait optimum. Surprisingly, we find no effect in the natural population of EDI-Cvi-0 (CRY2 V367M), an allele for which an effect was previously validated by introgression into a Eurasian line. Instead, our results suggest the previously observed effect of the EDI-Cvi-0 allele on flowering time likely depends on genetic background, due to an epistatic interaction. Altogether, our results provide an empirical example of the effects demographic history and selection has on trait architecture.
Glutarate regulates T cell metabolism and anti-tumour immunity
Authors: Eleanor Minogue, Pedro P. Cunha, Brennan J. Wadsworth, Guinevere L. Grice, Shiv K. Sah-Teli, Rob Hughes, David Bargiela, Alessandro Quaranta, Javier Zurita, Robin Antrobus, Pedro Velica, Laura Barbieri, Craig E. Wheelock, Peppi Koivunen, James A. Nathan, Iosifina P. Foskolou, Randall S. Johnson
Journal: Nature Metabolism (2023)

T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8
A stable and replicable neural signature of lifespan adversity in the adult brain
Authors: Nathalie E. Holz, Mariam Zabihi, Seyed Mostafa Kia, Maximillian Monninger, Pascal-M. Aggensteiner, Sebastian Siehl, Dorothea L. Floris, Arun L. W. Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Juliane H. Fröhner, Michael N. Smolka, Nilakshi Vaidya, Henrik Walter, Robert Whelan, Gunter Schumann, Andreas Meyer-Lindenberg, Daniel Brandeis, Jan K. Buitelaar, Frauke Nees, Christian Beckmann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Tobias Banaschewski, Andre F. Marquand
Journal: Nature Neuroscience (2023)

Abstract Environmental adversities constitute potent risk factors for psychiatric disorders. Evidence suggests the brain adapts to adversity, possibly in an adversity-type and region-specific manner. However, the long-term effects of adversity on brain structure and the association of individual neurobiological heterogeneity with behavior have yet to be elucidated. Here we estimated normative models of structural brain development based on a lifespan adversity profile in a longitudinal at-risk cohort aged 25 years ( n = 169). This revealed widespread morphometric changes in the brain, with partially adversity-specific features. This pattern was replicated at the age of 33 years ( n = 114) and in an independent sample at 22 years ( n = 115). At the individual level, greater volume contractions relative to the model were predictive of future anxiety. We show a stable neurobiological signature of adversity that persists into adulthood and emphasize the importance of considering individual-level rather than group-level predictions to explain emerging psychopathology.
Gluconeogenesis Flux in Metabolic Disease
Authors: Ankit Shah, Fredric E. Wondisford
Journal: Annual Review of Nutrition (2023)

Gluconeogenesis is a critical biosynthetic process that helps maintain whole-body glucose homeostasis and becomes altered in certain medical diseases. We review gluconeogenic flux in various medical diseases, including common metabolic disorders, hormonal imbalances, specific inborn genetic errors, and cancer. We discuss how the altered gluconeogenic activity contributes to disease pathogenesis using data from experiments using isotopic tracer and spectroscopy methodologies. These in vitro, animal, and human studies provide insights into the changes in circulating levels of available gluconeogenesis substrates and the efficiency of converting those substrates to glucose by gluconeogenic organs. We highlight ongoing knowledge gaps, discuss emerging research areas, and suggest future investigations. A better understanding of altered gluconeogenesis flux may ultimately identify novel and targeted treatment strategies for such diseases.
Efficacy of Dapagliflozin According to Geographic Location of Patients With Heart Failure
Authors: Toru Kondo, Xiaowen Wang, Mingming Yang, Pardeep S. Jhund, Brian L. Claggett, Muthiah Vaduganathan, Adrian F. Hernandez, Carolyn S.P. Lam, Silvio E. Inzucchi, Felipe A. Martinez, Rudolf A. de Boer, Mikhail N. Kosiborod, Akshay S. Desai, Lars Køber, Piotr Ponikowski, Marc S. Sabatine, Anna Maria Langkilde, Magnus Petersson, Natalia Zaozerska, Erasmus Bachus, Scott D. Solomon, John J.V. McMurray
Journal: Journal of the American College of Cardiology (2023)

Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region. The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.
A fetal wound healing program after intrauterine bile duct injury may contribute to biliary atresia
Authors: Iris E.M. de Jong, Mallory L. Hunt, Dongning Chen, Yu Du, Jessica Llewellyn, Kapish Gupta, David Li, Dorothea Erxleben, Felipe Rivas, Adam R. Hall, Emma E. Furth, Ali Naji, Chengyang Liu, Abhishek Dhand, Jason A. Burdick, Marcus G. Davey, Alan W. Flake, Robert J. Porte, Pierre A. Russo, J. William Gaynor, Rebecca G. Wells
Journal: Journal of Hepatology (2023)
A comprehensive description of kidney disease progression after acute kidney injury from a prospective, parallel-group cohort study
Authors: Kerry L. Horne, Daniela Viramontes-Hörner, Rebecca Packington, John Monaghan, Susan Shaw, Aleli Akani, Timothy Reilly, Thomas Trimble, Grazziela Figueredo, Nicholas M. Selby
Journal: Kidney International (2023)
Network Meta-Analysis of Initial Antithrombotic Regimens After Left Atrial Appendage Occlusion
Authors: Pedro E.P. Carvalho, Douglas M. Gewehr, Isabele A. Miyawaki, Alleh Nogueira, Nicole Felix, Philippe Garot, Arthur Darmon, Patrizio Mazzone, Alberto Preda, Bruno R. Nascimento, Luiz F. Kubrusly, Rhanderson Cardoso
Journal: Journal of the American College of Cardiology (2023)
Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease
Authors: Daniel S. Whittaker, Laila Akhmetova, Daniel Carlin, Haylie Romero, David K. Welsh, Christopher S. Colwell, Paula Desplats
Journal: Cell Metabolism (2023)

Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.
A unified pipeline for FISH spatial transcriptomics
Authors: Cecilia Cisar, Nicholas Keener, Mathew Ruffalo, Benedict Paten
Journal: Cell Genomics (2023)

High-throughput spatial transcriptomics has emerged as a powerful tool for investigating the spatial distribution of mRNA expression and its effects on cellular function. There is a lack of standardized tools for analyzing spatial transcriptomics data, leading many groups to write their own in-house tools that are often poorly documented and not generalizable. To address this, we have expanded and improved the starfish library and used those tools to create PIPEFISH, a semi-automated and generalizable pipeline that performs transcript annotation for fluorescence in situ hybridization (FISH)-based spatial transcriptomics. We used this pipeline to annotate transcript locations from three real datasets from three different common types of FISH image-based experiments, MERFISH, seqFISH, and targeted in situ sequencing (ISS), and verified that the results were high quality using the internal quality metrics of the pipeline and also a comparison with an orthogonal method of measuring RNA expression. PIPEFISH is a publicly available and open-source tool.
Osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting breast cancer secondary metastasis
Authors: Yutong Wu, Hongbo Ai, Yuhang Xi, Jiulin Tan, Ying Qu, Jianzhong Xu, Fei Luo, Ce Dou
Journal: Cell Reports Medicine (2023)

The bone microenvironment promotes cancer cell proliferation and dissemination. During periodic bone remodeling, osteoclasts undergo apoptosis, producing large numbers of apoptotic bodies (ABs). However, the biological role of osteoclast-derived ABs, which are residents of the bone-tumor niche, remains largely unknown. Here, we discover that AB-null MRL/lpr mice show resistance to breast cancer cell implantation, with more CD8+ T cell infiltrations and a higher survival rate. We uncover that the membranous Siglec15 on osteoclast-derived ABs binds with sialylated Toll-like receptor 2 (TLR2) and blocks downstream co-stimulatory signaling, leading to the inhibition of naive CD8+ T cell activation. In addition, our study shows that treatment with Siglec15 neutralizing antibodies significantly reduces the incidence of secondary metastases and improves the survival rate of mice with advanced breast cancer bone metastasis. Our findings reveal the immunosuppressive function of osteoclast-derived ABs in the bone-tumor niche and demonstrate the potential of Siglec15 as a common target for anti-resorption and immunotherapy.
Automatic intracranial abnormality detection and localization in head CT scans by learning from free-text reports
Authors: Aohan Liu, Yuchen Guo, Jinhao Lyu, Jing Xie, Feng Xu, Xin Lou, Jun-hai Yong, Qionghai Dai
Journal: Cell Reports Medicine (2023)

Deep learning has yielded promising results for medical image diagnosis but relies heavily on manual image annotations, which are expensive to acquire. We present Cross-DL, a cross-modality learning framework for intracranial abnormality detection and localization in head computed tomography (CT) scans by learning from free-text imaging reports. Cross-DL has a discretizer that automatically extracts discrete labels of abnormality types and locations from reports, which are utilized to train an image analyzer by a dynamic multi-instance learning approach. Benefiting from the low annotation cost and a consequent large-scale training set of 28,472 CT scans, Cross-DL achieves accurate performance, with an average area under the receiver operating characteristic curve (AUROC) of 0.956 (95% confidence interval: 0.952-0.959) in detecting 4 abnormality types in 17 regions while accurately localizing abnormalities at the voxel level. An intracranial hemorrhage classification experiment on the external dataset CQ500 achieves an AUROC of 0.928 (0.905-0.951). The model can also help review prioritization.
Olfactomedin 4 deletion exacerbates nonalcoholic fatty liver disease through P62-dependent mitophagy in mice
Authors: Shenghui Chen, Xinyu Wang, Zhening Liu, Jinghua Wang, Yanjun Guo, Qinqiu Wang, Hangkai Huang, Youming Li, Chaohui Yu, Chengfu Xu
Journal: Metabolism (2023)
C1q<sup>+</sup>tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion
Authors: Siyu Zhang, Wenbei Peng, Haolei Wang, Xuan Xiang, Linlin Ye, Xiaoshan Wei, Zihao Wang, Qianqian Xue, Long Chen, Yuan Su, Qiong Zhou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet.Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q)+ TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q+ TAMs.C1q+ TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q+ TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8+ T cells. Mechanistically, C1q+ TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q+ TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer.C1q+ TAMs impede antitumor effects of CD8+ T cells promoting MPE immunosuppression. Targeting C1q+ TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q+ TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.
Additive impact of diabetes and sarcopenia on all-cause and cardiovascular mortality: A longitudinal nationwide population-based study
Authors: Eyun Song, Soon Young Hwang, Min Jeong Park, Ahreum Jang, Kyeong Jin Kim, Ji Hee Yu, Nam Hoon Kim, Hye Jin Yoo, Ji A Seo, Sin Gon Kim, Nan Hee Kim, Sei Hyun Baik, Kyung Mook Choi
Journal: Metabolism (2023)
Intratumoral T-cell and B-cell receptor architecture associates with distinct immune tumor microenvironment features and clinical outcomes of anti-PD-1/L1 immunotherapy
Authors: Aimilia Schina, Zsofia Sztupinszki, Inge Marie Svane, Zoltan Szallasi, Göran Jönsson, Marco Donia
Journal: Journal for ImmunoTherapy of Cancer (2023)

Effective cooperation between B-cells and T-cells within the tumor microenvironment may lead to the regression of established tumors. B-cells and T-cells can recognize tumor antigens with exquisite specificity via their receptor complexes. Nevertheless, whether a diverse intratumoral B-cells and T-cell receptor (BCR, TCR) repertoire affects the tumor immune microenvironment (TIME) and clinical outcomes in patients treated with immunotherapy is unclear. We extracted information on BCR and TCR repertoire diversity from large clinical datasets and measured the association between immune receptor diversity features, the TIME, and clinical outcomes of patients treated with anti-PD-1/PD-L1 immunotherapy. In multiple tumor types, an increasingly diverse TCR repertoire was strongly associated with a highly activated TIME, while BCR diversity was more associated with antibody responses but not with the overall B-cell infiltration nor with measures related to intratumoral CD8+T cell activity. Neither TCR nor BCR diversity was independent prognostic biomarkers of survival across multiple cancer types. However, both TCR and BCR diversity improved the performance of predictive models combined with established biomarkers of response to immunotherapy. Overall, these data indicate a currently unexplored immunological role of intratumoral B-cells associated with BCR diversity and antibody responses but independent of classical anticancer T-cells intratumoral activities.
T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy
Authors: Bettzy Stephen, Joud Hajjar, Shrutii Sarda, Dzifa Yawa Duose, Jeffrey M Conroy, Carl Morrison, Anas Alshawa, Mingxuan Xu, Abdulrazzak Zarifa, Sapna P Patel, Ying Yuan, Evan Kwiatkowski, Linghua Wang, Jordi Rodon Ahnert, Siqing Fu, Funda Meric-Bernstam, Geoffrey M Lowman, Timothy Looney, Aung Naing
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.